Abstract 5108: Oscillatory calcium signal drives melanoma invasion and metastasis

Abstract

Abstract Ca2+ signaling has been increasingly implicated in cancer invasion and metastasis, and yet the underlying mechanisms remained largely unknown. Here, we report that STIM1- and Orai1- mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca2+ oscillation signals facilitate invadopodial precursor assembly by activating Pyk2 phosphorylation at tyrosine 402, which directly binds to and activates Src to promote invadopoium assembly. Disruption of Ca2+ oscillations inhibited invadopodium assembly. Futhermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodium. Mechanistically, Orai1 blockade inhibits the recycling of MT1-MMP to the plasma membrane and entraps MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca2+ -mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca2+ signals during melanoma invasion and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Jianwei Sun, Fujian Lu, Huifang He, Heping Cheng, Shengyu Yang. Oscillatory calcium signal drives melanoma invasion and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5108. doi:10.1158/1538-7445.AM2015-5108